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Intramural Papers of the Month

By Robin Arnette
March 2009

Maternal Obesity Increases the Risk of Neonatal Death

Researchers from NIEHS, Creighton University School of Medicine and the University of Nebraska Medical Center have found that during pregnancy, obese women had an increased risk of neonatal death and overall infant death. The team studied the association between maternal obesity and the risk of infant death by using the 1988 U.S. National Maternal and Infant Health Survey (NMIHS) data. The finding may represent a way to reduce infant mortality.

The National Center for Health Statistics conducted the NMIHS to study factors related to poor pregnancy outcome. The survey included a nationally representative sample of 9953 women who gave birth to live infants. Out of this sample size, 3309 of the women had late fetal deaths, while 5532 had infant deaths. After childbirth, the mothers were mailed questionnaires about reproductive history, life style, prenatal care, delivery, postpartum conditions, and neonatal and infant health. Medical records were obtained from prenatal care providers and hospitals.

The results indicated that obese women had a higher risk for neonatal death from pregnancy complications or disorders relating to short gestation and unspecified low birth rate. However, in non-obese women low weight gain may pose an increased risk of infant death.

Chen A, Feresu SA, Fernandez C, Rogan WJ (http://www.ncbi.nlm.nih.gov/pubmed/18813025?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor) Exit NIEHS. 2009. Maternal obesity and the risk of infant death in the United States. Epidemiology 20(1):74-81.

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The Involvement of UV Radiation in the Development of Dermatomyositis

The autoimmune disease dermatomyositis (DM) often causes a person's own antibodies to be directed toward Mi-2, an ATPase that serves as the core subunit of the nucleosome remodeling deacetylase (NuRD) complex. Exposure to ultraviolet (UV) radiation correlates with increased Mi-2 autoantigen and is implicated in the etiology of the disease although the exact mechanism remained unknown.

Researchers at NIEHS have determined that irradiating cell culture systems with UV increased protein expression levels of Mi-2, maximized Mi-2 levels one hour after irradiation and maintained its protein expression levels for up to 16 hours. The research team also found that following UV treatment, the Mi-2 mRNA was translated more efficiently through a regulatory element within the 5'-UTR region. Under these conditions the Mi-2 protein did not localize to DNA damage sites, suggesting an alternative mechanism to its autoantigenic activity.

The discovery represented a possible mechanism for the development of DM specific autoimmunity and provided a possible new regulatory action for Mi-2 and the NuRD complex.

Burd CJ, Kinyamu HK, Miller FW, Archer TK (http://www.ncbi.nlm.nih.gov/pubmed/18922793?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2008. UV radiation regulates Mi-2 through protein translation and stability. J Biol Chem 283(50):34976-34982.

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Fibroid Growth Differs Among Black and White Women

Fibroids, benign tumors of the uterus, are the leading cause of hysterectomies in the U.S. Black women suffer more severe symptoms and are at higher risk for hysterectomy than whites. A collaborative study between NIEHS and UNC, with support from Integrated Laboratory Systems, followed fibroid growth using MRIs. The researchers tracked the changes in size of 262 tumors from 72 women and found several surprises. Even though most of the women had multiple fibroids, each tumor grew at its own rate, and a large tumor was not necessarily a fast growing one. The study only followed pre-menopausal women, but, surprisingly, some of the tumors from young women in the study shrank. Fibroid growth rates did not differ between black and white women under age 35, but the tumor growth rate for black women over 35 did not slow with age as it did for white women.

Important implications of this study are: 1) large tumors can no longer be assumed to be rapidly growing tumors, 2) further study of the mechanisms that result in tumor shrinkage in premenopausal women may provide new strategies for treatment development, and 3) the absence of a growth-rate decline with age for tumors in black women may help explain the higher symptom burden they experience.

Peddada SD, Laughlin SK, Miner K, Guyon JP, Haneke K, Vahdat HL, Semelka RC, Kowalik A, Armao D, Davis B, Baird DD (http://www.ncbi.nlm.nih.gov/pubmed/19047643?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2008. Growth of uterine leiomyomata among premenopausal black and white women. Proc Natl Acad Sci USA 105(50):19887-19892.

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The Role of Activation-Induced Deaminase in Lupus

Lupus is an autoimmune disease in humans in which the body produces autoantibodies against itself that cause inflammation, pain and damage to various parts of the body. The MRL/lpr mouse is a good rodent model for lupus because it shares many characteristics of the disorder, specifically, the development of autoantibodies to double-stranded (ds) DNA.

Researchers at NIEHS studying MRL/lpr mice have determined that decreased levels of activation-induced deaminase (AID) in heterozygotes, a protein that triggers class switch recombination (CSR) and somatic hypermutation (SHM), resulted in a dramatic drop in the levels of high affinity anti-dsDNA antibodies. This event correlated with a significant decrease in the severity of lupus nephritis. The findings represent an important step in lupus research.

The research team studied the frequency of SHM and the rate of CSR in AID+/- MRL/lpr mice using ELISA, flow cytometry analysis and affinity assays.

Jiang C, Zhao ML, Diaz M (http://www.ncbi.nlm.nih.gov/pubmed/18624728?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2009. Activation-induced deaminase heterozygous MRL/lpr mice are delayed in the production of high-affinity pathogenic antibodies and in the development of lupus nephritis. Immunology 126(1):102-113.



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